Human interferon-α (IFN-α) is a vital biological factor that has a large market in antiviral and antitumor therapy. A class of cytokines that has antiviral, antiproliferative, and immunomodulatory properties. IFN-α was first described as a protein released by fibroblasts that cause paracrine resistance to lytic viral infection. Fibroblasts but also T cells, macrophages, plasmacytoid monocytes, DCs, and natural killer (NK) cells also release IFN-α.
These 12 interferon (IFN) sequences from the human gene database are classified into at least 8 subtypes - meaning that we have at least 8 IFN-α like genes. These genes direct IFN production in large numbers of Escherichia coli if not all. A chromosomal gene's sequence and its flanking sequence are the same as the inferred sequence of the cDNA of IFN-αl mRNA. There were no introns in the gene's code or non-code region.
Interferon-α (IFN-α) has been clinically demonstrated as an antiviral and antitumor therapy. It's these advantages that IFN-α brings to the table in modulating multiple cytokines and receptors that launch the host's immune system and deliver efficient antitumor and antiviral immunity.
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Human Interferon-α as Immunotherapeutic Protein
In vitro studies of the antiviral activities of IFN-α were originally performed in mammalian cell lines expressing viruses. Besides direct antiviral activity, these studies also demonstrated that IFN-α blocked cell proliferation quite powerfully. Since the majority of cell lines used in in vitro experiments were transformed, these early findings generated studies on the antitumor activity of IFN-α. IFN-α cures or kills disease - perhaps the direct intracellular activity of IFN-α should be weighed against the immunomodulatory activities. The research aiming to further clarify the immunomodulatory function will be important to future clinical immunotherapy use of IFN-α.
Fig. 1 Schematic diagram of the physiological activity of IFN-α (Brassard, D.; et al. 2002).
Tumor Immunity Activity of Human Interferon-α
The combined influence of IFN-αα on hematological tumors is greater than that on solid tumors, and the immune response to IFN-α therapy has been shown to be important for clinical anti-tumor activity. Early T-cell activation events are mediated by IFN-α inhibition, which can significantly suppress adjuvant arthritis in rats and slow delayed hypersensitivity responses and allergen-induced lymph node hyperplasia. IFN-α is multifunctional against tumors, offering a couple of options for cancer therapy by influencing immune system responses and anti-tumor immunity.
Immune Cell Activation
IFN-α could help natural killer cells (NK cells) and cytotoxic T lymphocytes (CTLs) better recognize and destroy tumor cells.
Anti-tumor Effect
Activating the expression of MHC (major histocompatibility complex) molecules on the surface of tumor cells, IFN-α makes it more likely that tumor cells will be seen by the immune system. Additionally, IFN-α can cause tumor cell death and tumor cell proliferation.
Inhibit Tumor Angiogenesis
IFN-α blocks tumor angiogenesis by deregulating the production of a few factors and inhibiting the progression of tumors and metastases.
Regulate Immune Microenvironment
IFN-α alters the makeup of immune cells in the tumor microenvironment and augments anti-tumor immunity. Alternatively, it can even suppress the function of immunosuppressive cells (eg, regulatory T cells and tumor-associated macrophages).
Human Interferon-α Signaling and Immune Responses
IFN-α activates both up and down transcription of a broad range of gene products, transcriptional activators, and other cytokines, so the effects of IFN-α treatment are sometimes characterized as polymorphic. The modulation of other cytokines is also one reason why it is hard to say precisely/directly how IFN-α affects the host immune system. And JAK/STAT is also mediated by several other signaling effector molecules such as IFN-α. It is not surprising, then, that IFN-α therapy has a pretty opaque direct biological effect. Studies via microarray and proteomic profiling have already started to study the nuanced cellular reactions induced by IFN-α and IFN-α treatment.
Human Interferon-α Modulates Adaptive Immune Responses
Res have also identified IFN-α as acting autocrinely on the movement of lymphocytes to activate adaptive immune responses. This is relevant for anti-infective and immunomodulatory roles during an immune response, as well as for recruiting T-cell, B-cell, and NK cell populations from the bone marrow to target secondary areas/tissues for presentation of antigen. It also releases NK-cell-generated cytokines into the localized area, as well as enhancing T and B cell activation where antigen-specific cells are few. It induces adaptive immunity during primary infection and makes it more likely that low-frequency antigen-specific cells will become active.
Conclusion
IFN-α can inhibit viral replication through multiple mechanisms, such as enhancing the antiviral state of cells, promoting the production of antiviral proteins, and interfering with viral gene expression. Human interferon-α can mobilize the body's immune system, enhance antitumor immune responses, and stimulate the activity of T cells and NK cells. IFN-α activity is a direct intracellular effect, including inhibition of viral replication. IFN-α activity is also important for immune cell function and plays a role in regulating the host's immune response to disease. In addition, IFN-α directly and indirectly acts on many cellular functions in the immune response to tumors and viral infections.
As an early response cytokine, IFN-α is expected to become a key initiating cytokine for immune antitumor and antiviral responses. Local effects on IFN-α expression include the activation of immediate and effective innate immune responses. IFN-α plays a key role in guiding the transition from innate immunity to adaptive immunity through multiple mechanisms, including controlling host Th1/Th2 responses and regulating CD8 CTL activity and memory.
References
- Brassard, D.; et al. Interferon-α as an immunotherapeutic protein.Journal of leukocyte biology. 2002, 71(4): 565-581.
- Adolf, G.; et al. Antigenic Structure of Human Interferon ω 1 (Interferon α II1): Comparison with Other Human Interferons. Journal of general virology. 1987, 68(6): 1669-1676.
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